Lipid formulations

In the BBB-PAMPA lipid formulation illustrated in Fig. 3.4, the diff values, defined as the difference log Pq-log Pi, range from 2.9 (morphine) to 4.2 (warfarin), somewhat similar to the values observed in the octanol-water system. However, it is premature to propose a pdiffi-A approximation, given the limited amount of data reported. With other lipid formulations, larger differences are usually observed. In Double-Sink PAM PA, and especially in hexadecane-PAMPA, transport of ionized drugs has not been reported [84]. 

Pouton, C. Formulation of poorly water-soluble drugs for oral administration Physicochemical and physiological issues and the lipid formulation classification system. Eur. J. Pharm. Sci. 2006, 29, 278-287. 

Itraconazole 200 mg PO daily for 6-12 weeks Lipid formulation may be more effective... 

Fusariosis Lipid formulations of amphotericin B OR Voriconazole 6 mg/kg q12hour for 1 day, then 4 mg/kg q12hour OR Posaconazole 200 mg PO qid for 14 days, then 200 mg PO q12hour OR Combination therapy ... 

Several enveloped viruses, and some physical gene transfer techniques such as electroporation, deliver the nucleic acid into the cell by direct crossing of the cell membrane. Lipid-based, enveloped systems can do this by a physiological, selfsealing membrane fusion process, avoiding physical damage of the cell membrane. For cationic lipid-mediated delivery of siRNA, most material is taken up by endo-cytotic processes. Recently, direct transfer into the cytosol has been demonstrated to be the bioactive delivery principle for certain siRNA lipid formulations [151]. 

For patients unable to tolerate a full course of amphotericin B, consider lipid formulations of amphotericin B or fluconazole >800 mg orally daily. 

Amphotericin B is generally preferred as initial therapy in patients with rapidly progressive disease, whereas azoles are generally preferred in patients with subacute or chronic presentations. Lipid formulations of amphotericin B have not been extensively studied for coccidioidomycosis but can offer a means of giving more drug with less toxicity. Treatments for primary respiratory disease (mainly symptomatic patients) are 3- to 6-month courses of therapy. 

CNS disease Lipid formulation of amphotericin BIV 3-6 mg/kg/day x 6-10 weeks (Note Induction therapy with azoles alone is discouraged.) Amphotericin Brf IV 0.7-1 mg/kg/day + flucytosine 100 mg/kg/ day orally x 2 wk, followed by fluconazole 400 mg orally daily for a minimum of 10 weeks (in patients intolerant to fluconazole, substitute itraconazole 200-400 mg orally daily) or Amphotericin B IV 0.7-1 mg/kg/day + 5-flucytosine 100 mg/kj day orally x 6-10 weeks or Amphotericin Brf IV 0.7-1 mg/kg/day x 10 weeks Refractory disease Intrathecal or intraventricular amphotericin B (continued)... 

In patients with significant renal disease, lipid formulations of amphotericin B can be substituted for deoxycholate amphotericin B... 

Lipid formulation of amphotericin B IV 3-5 m kg/day Chronic disseminated candidiasis Treatment duration Until calcification or resolution of lesions (hepatosplenic candidiasis) stable patients Fluconazole IV/po 6 mg/kg/day... 

When several experiments will be performed using the same lipid formulation, greater consistency will be achieved if each LUV sample is prepared... 

The aim of the research carried out in our laboratory was to develop a lipid formulation that could be manufactured by a simple and reproducible procedure. In particular, we wanted to produce phospholipid-based particles with a high AmB loading coupled to a small particle size. 

For the purposes of comparison, commercial AmB-lipid formulations were obtained as follows. Amphotec was obtained from Intermune (U.S.A.). AmBisome and Abelcet were kind gifts from Gilead Sciences (Foster City, California, U.S.A.) and Zedeus Pharma (Versailles, France), respectively. Ampholiposomes (cationic oligolameller liposomes containing AmB) were supplied by the Pharmacie Centrale des Hopitaux (Paris, France). 

The UV spectra of AmB varied according to its proportion in the lipid formulation, indicating that its self-aggregation was limited by its complexa-tion with the phospholipids. These results were confirmed by circular dichroism (CD). When the AmB-lipid complexes containing 10% to 50% w/w of AmB were examined (Fig. 4), the dichroic doublet characterizing the aggregation state of AmB, centered on 335 nm, was still observed but... 

AmB solubilized in DMSO and dispersed in PBS provoked 50% hemolysis of human erythrocytes at 3.5mg/L of AmB. Fungizone and AmB prepared by the same process as LC-AmB but without lipids were slightly less toxic (Hbso 5mg/L). All the lipid formulations caused less than 50% hemolysis at the highest concentration tested (lOOmg/L). 

One factor determining toxicity of AmB formulations is the form in which the antibiotic is released monomeric or aggregated because only self-associated AmB can complex cholesterol in eukaryote membranes (25). The differential toxicity of the lipid formulations toward macrophages could be related to their stability in the culture medium. For example, the Ampho-liposome formulation, which is destabilized in the presence of serum (24), has... 

The results of the chronic administration study indicate that LC-AmB does not induce any new toxicity and that its side effects are the same as those produced by the conventional formulation (Fungizone) and a commercial lipid formulation (Abelcet) but that they appear at higher doses. This difference is probably due to both the stability of the formulation, preventing rapid release of AmB as aggregates or transfer to lipoproteins, and its size difference with Abelcet, which could lead to less rapid uptake by phagocytic cells. These encouraging results with respect to toxicity prompted us to test the efficacy of the formulation. For this, we chose to look at in vitro and in vivo models of Leishmaniasis, as well as the immuno-modulating properties of AmB. 

Larabi M, et al. New lipid formulation of amphotericin B spectral and microscopic analysis. Biochim Biophys Acta 2004 1664 172. 

Automated Screening of Cationic Lipid Formulations for Transfection... 

Feigner JH, Kumar R, Sridhar CN, et al. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J Biol Chem 1994 269(4) 2550-2561. 

Lipid formulations of amphotericin B have been shown to reduce the severe kidney toxicity of amphotericin B and are indicated in patients with renal impairment or when unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses. 

Renai function impairment Use amphotericin B desoxycholate with care in patients with reduced renal function frequent monitoring is recommended (see Precautions). Lipid formulations have been reported to overcome most problems of chronic nephrotoxicity, even in patients with impaired renal function following previous treatment with amphotericin B desoxycholate. 

Invasive aspergillosis For the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (ie, amphotericin B, lipid formulations of amphotericin B, itraconazole). Caspofungin has not been studied as initial therapy for invasive aspergillosis. 

Wong-Beringer A, Jacobs RA, and Gugliehno BJ. Lipid formulations of amphotericin B Clinical efficacy and toxicities. CUn Infect Dis 1998 27 603-618. 

Table 48- -1 Properties of Conventional Amphotericin and Some Lipid Formulations.1 ...

Three such formulations are now available and have differing pharmacologic properties as summarized in Table 48-1. Although clinical trials have demonstrated different renal and infusion-related toxicities for these preparations compared with regular amphotericin B, there are no trials comparing the different formulations with each other. Limited studies have suggested at best a moderate improvement in the clinical efficacy of the lipid formulations compared with conventional amphotericin B. Because the lipid preparations are much more expensive, their use is usually restricted to patients intolerant to, or not responding to, conventional amphotericin treatment. 

Lipid formulations Lower toxicity, higher doses can be used ... 

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